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While infected cells have been extensively studied, the responses of uninfected bystander macrophages in the same microenvironment remain poorly understood. Here, we demonstrate that\n                      <jats:italic toggle=\"yes\">Mtb<\/jats:italic>\n                      infection triggers broad epigenetic and transcriptional reprogramming in bystander macrophages, predominantly via interleukin-1\u03b2-dependent nuclear factor-\u03baB signaling from infected cells. These bystander cells acquire active chromatin marks, exhibit distinct gene expression profiles, and display enhanced responsiveness to subsequent immune challenges. Functionally, bystander macrophages restrict intracellular\n                      <jats:italic toggle=\"yes\">Mtb<\/jats:italic>\n                      growth and also show increased responsiveness to heterologous stimuli resembling trained immunity. Our findings uncover a previously underappreciated mechanism of intercellular communication during infection, wherein\n                      <jats:italic toggle=\"yes\">Mtb<\/jats:italic>\n                      -infected macrophages prime neighboring uninfected cells for enhanced defense. This work defines cytokine-mediated reprogramming of both infected and bystander cell subpopulations, and identifies bystander cells as active participants in shaping the population-wide host immune landscape. These insights have implications for understanding innate immune memory and developing strategies to modulate host defense in tuberculosis and other infections.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>\n                      This study reveals an underappreciated role for uninfected bystander macrophages in host defense against\n                      <jats:italic toggle=\"yes\">Mycobacterium tuberculosis<\/jats:italic>\n                      (\n                      <jats:italic toggle=\"yes\">Mtb<\/jats:italic>\n                      ). We demonstrate that\n                      <jats:italic toggle=\"yes\">Mtb<\/jats:italic>\n                      -infected macrophages trigger interleukin-1\u03b2-mediated epigenetic training in neighboring bystander cells, priming them for enhanced immune responses. These trained macrophages exhibit heightened antimicrobial activity and restrict\n                      <jats:italic toggle=\"yes\">Mtb<\/jats:italic>\n                      growth upon subsequent infection. By uncovering a mechanism through which immune memory-like responses propagate beyond infected cells, our findings redefine the cellular scope of innate immunity during tuberculosis and identify new opportunities to boost host defense through intercellular signaling and epigenetic reprogramming.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/mbio.01214-26","type":"journal-article","created":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T13:06:11Z","timestamp":1784639171000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["<i>Mycobacterium tuberculosis<\/i>\n                    infection triggers IL-1\u03b2-dependent epigenetic training in bystander 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